Hair is composed of keratin, a tough and insoluble protein. Each individual hair comprises a cylindrical shaft and a root, and is contained in a follicle, a flask-like depression in the skin. The bottom of the follicle contains a finger-like projection termed the papilla, which consists of connective tissue from which hair grows, and through which blood vessels supply the cells with nourishment. The shaft is the part of the hair that extends outwards from the skin surface, and the root is the part of the hair that remains buried beneath the skin surface. The base of the root expands into a hair bulb, which rests upon the papilla. Cells from which the hair is produced grow in the bulb of the follicle and are extruded in the form of fibers as the cells proliferate in the follicle. “Hair growth” refers to the formation and elongation of the hair fiber by the dividing cells.
Hair growth occurs by a cycle of activity that is divided into three stages: anagen, catagen, and telogen. Anagen is the active phase, during which the epidermal stem cells of the dermal papilla divide rapidly. Daughter cells move upward and differentiate to form the concentric layers of the hair itself. Catagen is the transitional stage, where follicular stem cell division has ceased. Telogen is the resting stage, where the hair is retained for several weeks before an emerging new hair developing below it dislodges the telogen-phase shaft from its follicle. Hair is thus undergoing constant renewal. Among approximately 125,000-150,000 hairs on a scalp, at any given time approximately ten percent are at rest and will be replaced within a few months.
The location in which hair originates affects its characteristics. Eyebrow hair, for example, differs from scalp hair in several respects. For eyebrow hair, the growth cycle is very short, typically completing in approximately 4 months, whereas the scalp hair growth cycle requires 3 to 4 years to complete. This difference in growth cycle duration is the reason eyebrow hairs are much shorter than scalp hairs. Another distinction is that eyebrow hair emerges from the follicle at a very acute angle, which produces growth that is essentially parallel to the skin surface. By contrast, the angle between scalp hair and the skin can be 45 degrees or more. Eyebrow hairs also grow as single strands, whereas several hair strands typically arise from a single follicle on the scalp.
Disruption of the hair growth cycle causes alopecia (hair loss), a condition that affects millions of men and women. Alopecia encompasses any loss of hair, including not only from the scalp, but also from other areas such as the eyebrows. Certain chemotherapeutic agents can induce alopecia. Chemotherapy works by damaging the structure or metabolism of rapidly dividing cells. Unfortunately, chemotherapeutic agents do not selectively target only diseased or otherwise undesirable cells, such as the rapidly proliferating tissue of a cancerous tumor, and instead also attack normal cells that multiply rapidly in the body, including those in bone marrow, the lining of the mouth, stomach, and hair follicles.
Due to its long anagen phase, the scalp is a common location for chemotherapy-induced hair loss. Hairs of the beard, eyebrows, eyelashes, axillary regions, and pubic regions are also variably affected by chemotherapy. During anagen, cells in the bulb of the hair follicle exhibit the greatest activity in building up the hair shaft. Chemotherapeutic agents impair mitotic and metabolic processes in actively growing hair follicles and lead to a weakening of the partially keratinized, proximal portion of the hair shaft, resulting in a thinning of the hair shaft, which becomes fragile and susceptible to breakage with minimal influence (anagen effluvium). Evidence exists suggesting that telogen hair is also lost during chemotherapy (telogen effluvium). Braun-Falco, Dynamics of normal and pathological hair growth, ARCH. KLIN. EXP. DERMATOL. 227(1):419-52 (1966).
In human skin, alopecia can start at any time after initiation of chemotherapy, but hair loss typically occurs 2 to 4 weeks after treatment begins. Hubbard, Chemotherapy-induced alopecia, CLIN. ONCOL. 4:387-457 (1985); Hussein, Chemotherapy-induced alopecia: New developments, SOUTHERN MED. J. 86:489-496 (1993). The rate and pattern of hair shedding varies with the degree to which anagen effluvium and telogen effluvium occur. Accordingly, the hair may fall out very quickly in clumps or it may fall out gradually.
The extent of chemotherapy-induced hair loss depends on the drug being used, how long the drug is used, and whether other treatments (such as radiation) are concurrently employed. There are four major classes of chemotherapeutic agents that can induce alopecia, with the extent of induced hair loss differing across the classes: antimicrotubule agents (e.g. paclitaxel (trade name Taxol®)); topoisomerase inhibitors (e.g. doxorubicin); alkylators (e.g. cyclophosphamide); and antimetabolites (e.g. 5-fluorouracil plus leucovorin). Drugs with high potential for inducing alopecia include adriamycin, cyclophosphamide daunorubicin, docetaxel (trade name Taxotere®), epirubicin, etoposide, ifosphamide, irinotecan, paclitaxel, topotecan, vindesine, and vinorelbine. Taxol® typically induces complete hair loss, including scalp and eyebrows. Adriamycin causes complete hair loss on the scalp, and very often causes loss of eyebrows in patients. Chemotherapeutic agents such as methotrexate, cytoxan, carboplatin, and 5-fluorouracil can cause hair loss in some patients but not others. There are many similar examples of chemotherapeutic agents that can induce partial or complete hair loss in various locations throughout the body. The overall incidence of chemotherapy-induced hair loss is estimated to be 65 percent. Trueb, Chemotherapy-induced alopecia, SEMIN. CUTAN. MED. SURG. 28(1):11-14 (2009).
Chemotherapy-induced alopecia can be profoundly traumatic, and ranks among the most psychologically devastating side-effects of cancer treatment. Kiebert et al. Effect of perioperative chemotherapy on the quality of life of patients with early breast cancer, EUR. J. CANCER 26:1038-1042 (1990); Macquart-Moulin et al. Discordance between physicians' estimations and breast cancer patients' self-assessments of side-effects of chemotherapy: an issue for quality of care, BR. J. CANCER 76:1640-1645 (1997). Indeed, studies show that for many women, losing their hair is more emotionally distressing than losing a breast, because one can conceal loss of a breast but hair loss is so obvious and apparent. For men as well, hair loss during chemotherapy can negatively affect perceptions of masculinity, and loss of eyebrows in particular provides an unwelcome signal of having cancer. More than 80 percent of patients who receive chemotherapy consider hair loss to be the worst aspect of their treatment (Kiebert et al.; Macquart-Moulin et al.), and 8 percent of female cancer patients would even decline treatment for fear of that side-effect. McGarvey et al., Psychological sequelae and alopecia among women with cancer, CANCER PRACT. 9(6):283-289 (2001); Munstedt et al., Changes in self-concept and body image during alopecia induced cancer chemotherapy, SUPPORT CARE CANCER 5(2):139-143 (1997). Although cranial prostheses (wigs) sometimes can be used to conceal loss of scalp hair, it is far more difficult to conceal loss of other facial hair, such as eyebrows. Eyebrows are a critical facial feature that serve to frame the eyes (the single most important facial element) and they convey key non-verbal information.
Though the structure and growth cycle of hair is well known, the exact mechanism(s) by which chemotherapeutic agents cause hair loss is not well understood. Although morphological changes that occur in hair follicles during chemotherapy were initially described in the early 1960s, there has been little progress in elucidating the mechanism(s) underlying such morphological changes.
Several diverse measures have been suggested for limiting or preventing chemotherapy-induced alopecia. Some researchers suggest that massive induction of apoptosis (a process of programmed cell death (PCD) that may occur in multi-cellular organisms) in the hair follicle is one mechanism by which chemotherapeutic agents damage growing hair follicles. These researchers propose that a pretreatment with topical calcitriol-analogs can suppress chemotherapy-induced apoptosis in vivo. Schilli et al., Reduction of Intrafollicular Apoptosis in Chemotherapy-Induced Alopecia by Topical Calcitriol-Analogs, J. INVESTIGATIVE DERM. 111:598-604 (1998). However, topical application of 1,25-dihydroxyvitamin D3 failed to prevent or retard hair loss in human scalp after administration of cyclophopshamide. Hidalgo et al., A phase I trial of topical topitriol (calcitriol, 1,25-dihydroxyvitamin D3) to prevent chemotherapy-induced alopecia, ANTICANCER DRUGS 10:393-395 (1999).
Other investigators suggest that cleansing follicle openings of sebum may reduce hair loss and reduce the time necessary for hair re-growth in cancer patients who undergo chemotherapy. For example, U.S. Pat. No. 6,139,828 to McCullough discloses compositions for cleansing the scalp and hair follicles. However, the disclosed compositions include anionic surfactants, which can be harsh and irritating. Moreover, the disclosure provides only a single example of use of the claimed compositions in a patient undergoing chemotherapy. Though that example suggests that the patient experienced hair re-growth while continuing chemotherapy and radiation treatments, the disclosure provides no information regarding the patient's previous or current chemotherapy regimen. Because certain chemotherapeutic agents do not cause hair loss, it is not clear whether that patient experienced hair re-growth due to application of the disclosed composition, or instead simply due to natural hair re-growth where the presently-employed chemotherapeutic agent was one that did not induce hair loss. Furthermore, the disclosure nowhere discusses or exemplifies preventing (as opposed to reducing) hair loss in chemotherapy patients, and nowhere discusses or exemplifies reducing or preventing eyebrow loss.
Still other researchers suggest that scalp cooling may be effective in preventing hair loss in patients treated with certain chemotherapeutic agents. Such proponents contend that cooling the scalp to a temperature that produces a subcutaneous temperature of 20° C. (68° F.) constricts blood supply to hair follicles, preventing high chemotherapy dose delivery during the initial phase of treatment, and reducing metabolic rate of hair follicle cells. However, such treatment can be uncomfortable for a patient to endure. Moreover, scalp cooling does not prevent loss of other facial hair, such as eyebrows.
Still further methods that do not interact directly with existing hair follicles have also been proposed for concealing hair loss, and in particular eyebrow loss. For example, micropigmentation (tattooing) is sometimes used to simulate eyebrows that have been permanently lost. Micrograft transplants can also sometimes be used to restore eyebrows. However, such methods are time-consuming, often painful, and expensive.
As the discussion above demonstrates, previously proposed treatments for preventing chemotherapy-induced hair loss are uncertain and unsatisfactory in many respects. So far, no satisfactory composition or method exists for limiting or preventing chemotherapy-induced alopecia in humans. Accordingly, there remains a need for compositions and methods for preventing hair loss in patients undergoing chemotherapy, and in particular for preventing eyebrow loss in such patients.